Compositions and methods for controlling drug loss and delivery in transdermal drug delivery systems

ABSTRACT

A transdermal delivery system is provided for the topical application of one or more active agents contained in one or more polymeric and/or adhesive carrier layers, proximate to a non-drug containing polymeric and/or adhesive coating that is applied to either the transdermal system&#39;s backing or release liner. The transdermal delivery device is manufactured to optimize drug loading while providing desirable adhesion to skin or mucosa as well as providing modulation of the drug delivery and profile.

In accordance with 35 U.S.C. §119 (e), the benefit of provisionalapplication 60/515,306, filed Oct. 28, 2003, is hereby claimed. Theentire contents of this provisional application are incorporated hereinby reference.

TECHNICAL FIELD

This invention relates generally to transdermal drug delivery systems,and more particularly to pharmaceutically acceptable adhesive matrixcompositions. The invention additionally relates to transdermal drugdelivery systems where the drug permeation, delivery rates and profilescan be selectively modulated within the transdermal drug deliverysystem.

The present invention relates to transdermal delivery systems, theirmethod of making and method of use. In particular, the present inventionis directed to a transdermal drug delivery system for the topicalapplication of one or more active agents contained in one or morepolymeric and/or adhesive carrier layers, proximate to a non-drugcontaining polymeric and/or adhesive coating that is applied to eitherthe transdermal system's backing or release liner. The adhesive coatedbacking or release liner is processed or manufactured separately fromthe polymeric and/or adhesive drug carrier layers to prevent or minimizeloss of drug or other system components, and combined prior to topicalapplication. The drug delivery rate and profile can be furthercontrolled by adjusting certain characteristics of the polymers and/oradhesives themselves or of the method of making the system, relative tothe active agent's properties in this transdermal system.

BACKGROUND OF THE INVENTION

The use of a transdermal drug delivery system as a means foradministering therapeutically effective amounts of an active agent iswell known in the art. Transdermal devices or systems can be categorizedin many different ways, but those commonly called transdermal patches,incorporate the active agent into a carrier, usually a polymeric and/ora pressure-sensitive adhesive formulation.

Many factors influence the design and performance of such drug deliverydevices, such as the individual drugs themselves, the physical/chemicalcharacteristics of the system's components themselves and theirperformance/behavior relative to other system components once combined,external/environmental conditions during manufacturing and storagethereafter, the properties of the topical site of application, thedesired rate of drug delivery and onset, the drug delivery profile, andthe intended duration of delivery. Cost, appearance, size and ease ofmanufacturing are also important considerations. The ability to delivera therapeutically effective amount of the drug in accordance with theintended therapy or treatment is the goal.

The simplest in design is one in which the drug is incorporated into apressure-sensitive adhesive carrier layer, each surface of which isaffixed to a polymeric film/layer—one serving as the backing (to anchorthe carrier layer and control passage of environmental influences in andsystem components out during use) and the other serving as a removableliner (to protect the carrier layer prior to use but removed upontopical application of the carrier layer). However, when addressing allthe design and performance factors and considerations to achieve thegoal, this system alone cannot always provide the best method.

In this regard, a drug's delivery rate is affected by its degree ofsaturation and solubility in the carrier composition. Depending on theactive agent itself or the dosage necessary to be therapeuticallyeffective, the amount of drug needed to be incorporated into a single,adhesive carrier or matrix composition (i.e., drug loading) canadversely affect or be adversely affected by, such carrier or matrix.

Drug carrier compositions typically require one or more processingsolvents, usually organic solvents, in which to incorporate the activeagent and/or allow the polymeric/adhesive carrier to be more easilycoated onto a backing or release liner. Removal of such solvents isnecessary for avoiding problems associated with residual solventamounts, such as irritation at the topical site of application, drugdegradation, drug instability, loss of adhesive or cohesive propertiesimpacting attachment of the system to the user and loss of desireddelivery amount or rate. Solvent removal requires that elevatedtemperatures be applied to the carrier composition to evaporate suchsolvents. But at the same time, removal of solvents by use of elevatedtemperatures can also remove or evaporate other desirable components,such as the active agent and drug permeation enhancers. Their loss caneven occur at temperatures below which such components may otherwisevolatilize by virtue of their interaction with each other and with theother carrier components (relative volalitility or reactivity).

This is particularly problematic for drugs that are controlledsubstances (for which the Food and Drug Administration requires strictaccounting for during the manufacturing process) and/or drugs that haverelatively low boiling or melting points, such as low molecular weightdrugs and drugs in their free base form.

Another problem often encountered with low molecular weight drugs,particularly those that are liquid at or near room temperature, is theplasticizing effect that such drugs have on the carrier polymers in thetransdermal drug delivery system. Namely, the composition becomes “leggyor gummy” resulting in sufficient loss of adhesive and/or cohesiveproperties and therefore unsuitable for sticking to the skin or mucosaof the user. While using low drug concentrations may decrease thedeleterious affects to the carrier's adhesive or cohesive properties,low concentration can result in difficulties in achieving an acceptabledelivery rate and the drug may still be lost during processing.Similarly, increasing polymer concentrations by increasing thickness orsurface area of the carrier composition provides little flexibility ineffectively controlling the release rate of a variety of drugs. It wouldtherefore be worthwhile to provide a transdermal delivery system, whichallows the adhesive characteristics to be maintained in thedrug-containing layer while providing desired control of delivery rateand profile of the system.

Formulating with low molecular weight drugs that are liquid at or nearroom temperatures is further particularly difficult in adhesive carrierlayer compositions because such drugs more readily or easily permeateskin or mucosa. Such systems often cannot be adequately optimized tocontrol onset of delivery (i.e., slow down or retard) and/or maintaindelivery for an extended duration of delivery without compromising otherdesign and performance factors and considerations.

With respect to d-amphetamine in free base form, a particularlypreferred low molecular weight drug that is liquid at or near roomtemperatures, multiple concerns arise when manufacturing with processingsolvents. The drug is volatile at room temperature. The drug degrades inthe presence of certain solvents, particularly ethyl acetate. The drugdegrades into the carbonate form in the presence of carbon dioxidecommonly found in atmospheric air. Accordingly, manufacturing atransdermal system using processing solvents and effectively deliversuch a drug is even more problematic.

Additionally, transdermal carrier compositions based on acrylicpressure-sensitive adhesive polymers are often preferred for theirability to incorporate or solubilize many drugs. In order to provide foradequate wear properties and drug release from the composition,acrylic-based pressure-sensitive adhesives are typically polymerizedwith functional monomers to provide functional groups on theacrylic-based adhesive. A problem associated with the use of suchacrylic-based polymers with functional groups is that due to thegenerally high solubility of the drug, a large amount of drug generallymust be incorporated into the composition to saturate it and provide anadequate drug release to the skin of the user. In use with low molecularweight drugs or controlled substances, the loss of the drug in themanufacturing process again can be a significant problem.

Attempts have been made to utilize rate controlling membranes and/ormultiple layers, and to dissolve or suspend certain drugs inthermoplastic type carrier compositions without the use of solvents.These drug delivery devices generally do not allow a great amount offlexibility in effectively controlling the release rate of a variety ofdrugs, which in turn also severely limits their therapeutic application,and are expensive or burdensome to manufacture. Moreover, multipleadhesive layers are often required to affix the other layers ormembranes to each other, and/or to the site of topical application.

Thus, it would therefore be desirable to provide a system for use withmany types of drugs, in which the permeation rate and profile can beeasily adjusted while providing an active agent-containing carriercomposition formulated in a simple and cost effective manner. It wouldbe further advantageous to avoid drug loss encountered in manufacturingmethods requiring high temperature heating or drying after addition of adrug to the carrier composition.

SUMMARY OF THE INVENTION

Based upon the foregoing, it is an object of the present invention toovercome the limitations of the prior transdermal systems, and toprovide a transdermal drug delivery system which allows selectivemodulation of drug permeation and delivery rates and profiles.

Another object is to provide a transdermal system, which is simple andinexpensive to manufacture, while preventing or minimizing drug lossand/or other volatile components in the composition. The presentinvention provides a transdermal drug delivery system for the topicalapplication of one or more active agents contained in one or morepolymeric and/or adhesive carrier layers, proximate to a non-drugcontaining polymeric and/or adhesive coating that is applied to eitherthe transdermal system's backing or release liner, manufactured tooptimize drug loading while providing desirable adhesion to skin ormucosa as well as providing modulation of the drug delivery and profile.

The invention is further directed to a transdermal delivery systemcomprising a backing composite comprising a non-drug containingpolymeric and/or adhesive coating, which may contain low boiling pointor volatile components such as permeation enhancers, affixed or appliedto a drug-impermeable layer. An active agent carrier layer comprising apressure-sensitive adhesive composition and a drug incorporated thereinis affixed to the backing composite. The polymeric coating is designedto provide control of permeation rate, onset and profile of the activeagent from the system. The agent-carrier composition may comprise one ormore layers. The agent-carrier composition may comprise at least onelayer formed of a blend of at least one acrylic-based polymer and atleast one silicone-based polymer, to serve as a pressure-sensitiveadhesive composition for applying the system to the dermis, or a blendof acrylic-based polymers. The non-drug containing acrylic-based orother polymer coating designed to interact with the drug compositionlayer(s).

The invention is also directed to compositions and methods ofmanufacturing a transdermal delivery system prepared by controlling (a)the amounts of the per cent solids of the adhesives, (b) the amounts ofprocessing solvents, and (c) the amounts and types of enhancers, used intransdermal systems incorporating relatively volatile or reactive drugsor hydrophillic drugs when used with volatile or reactive enhancers.

The invention is also directed to compositions and methods ofcontrolling drug delivery rates, onset and profiles of at least oneactive agent in a transdermal delivery system, comprising the use of anon-drug containing acrylic-based polymer and/or adhesive coating onesurface of which is applied to either the transdermal system's backingor release liner and the other surface is affixed to a drug containingcarrier composition layer, wherein the delivery rate, onset of delivery(lag time) and delivery profile of a drug may be selectively modulatedby one or more of (a) increasing or decreasing the thickness or coatweight of the acrylic-based polymer and/or adhesive coating per cm² asapplied to the backing or release liner of the system, (b) manipulatingthe moiety or functionality of the acrylic-based polymer and/or adhesivecoating, and (c) manipulating the monomeric composition and/or ratios ofthe acrylic-based polymer and/or adhesive coating. Either the non-drugcontaining coating or the carrier composition must also be apressure-sensitive adhesive when used as area of attachment to the skinor mucosa of the user. The drug carrier composition may be comprised of(a) one or more acrylic-based polymers having one or more functionalityor (b) one or more silicone-based polymers having one or more silanolcontents (capping) and/or resin to polymer ratios, alone or incombination, and are present in proportions to provide a desiredsolubility for the drug. Further manipulation of drug delivery, onsetand profiles can be achieved by varying the concentrations of the drugin the drug-loaded carrier.

For a better understanding of the present invention, together with otherand further objects thereof, reference is made to the followingdescription, taken in conjunction with the accompanying drawings, andits scope will be pointed out in the appending claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. shows a schematic cross-sectional view of a transdermal deliverydevice according to an embodiment of the invention prior to use.

FIG. 2 shows a schematic cross-section of the agent-carrier assembly andbacking assembly according to the embodiment of the present invention asshown in FIG. 1, prior to lamination together.

FIG. 3 is a graphic representation of the effects on drug delivery,onset and profile of d-Amphetamine with different proportions ofnon-functional, acrylic-based adhesives in the polymeric coating.

FIG. 4 is a graphic representation of the effects on drug delivery,onset and profile of d-Amphetamine with varying concentrations ofcarboxy functional monomers in acrylic-based adhesives in the polymericcoating.

FIG. 5 is a graphic representation of the effects on drug delivery,onset and profile of d-Amphetamine with varying coat weights of anacrylic-based adhesive coating.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the following description, embodiments of the invention are setforth, and terms are used in describing such embodiments, wherein:

The term “topical” or “topically” is used herein in its conventionalmeaning as referring to direct contact with an anatomical site orsurface area on a mammal including skin, teeth, nails and mucosa.

The term “mucosa” as used herein means any moist anatomical membrane orsurface on a mammal such as oral, buccal, vaginal, rectal, nasal orophthalmic surfaces. Similarly, “skin” is meant to include mucosa, whichfurther includes oral, buccal, nasal, rectal and vaginal mucosa.

The term “transdermal” refers to delivery, administration or applicationof a drug by means of direct contact with tissue, such as skin ormucosa. Such delivery, administration or application is also known aspercutaneous, dermal, transmucosal and buccal.

As used herein, the terms “blend” and “mixture” are used herein to meanthat there is no, or substantially no, chemical reaction or crosslinking(other than simple H-bonding) between the different polymers in thepolymer matrix. However, crosslinking between a single polymer componentis fully contemplated to be within the scope of the present invention.

The term “adhesive” means a substance, inorganic or organic, natural orsynthetic that is capable of surface attachment at the intended topicalapplication site by itself or functions as an adhesive by admixture withtackifiers, plasticizers, cross-linking agents or other additives. Inthe most preferred embodiment, the carrier of the present invention is a“pressure-sensitive adhesive” which refers to a viscoelastic materialwhich adheres instantaneously to most substrates with the application ofvery slight pressure and remains permanently tacky. A polymer or dermalcomposition is a pressure-sensitive adhesive within the meaning of theterm as used herein if it has the adhesive properties of apressure-sensitive adhesive per se or functions as a pressure-sensitiveadhesive by admixture with tackifiers, plasticizers, cross-linkingagents or other additives.

As used herein, a “polymer composition of two or more polymers” isdefined as a physical blend of at least two polymers and can include 3or more polymers. The two or more polymers may include the acrylic-basedpolymers described herein and can optionally include other polymersdiscussed more fully below.

The term “acrylic-based” polymer is defined as any polyacrylate,polyacrylic, acrylate and acrylic polymer. The acrylic-based polymerscan be any of the homopolymers, copolymers, terpolymers, and the like ofvarious acrylic acids or esters. The acrylic-based polymers useful inpracticing the invention are polymers of one or more monomers of acrylicacids and other copolymerizable monomers. The acrylic-based polymersalso include copolymers of alkyl acrylates and/or methacrylates and/orcopolymerizable secondary monomers. Acrylic-based polymers withfunctional groups as described more fully below, are copolymerized withfunctional monomers.

As used herein, “functionality” is broadly defined as a measure of thetype and quantity of functional groups that a particular acrylic-basedpolymer has. This definition also encompasses acrylic-based polymershaving no or substantially no functional groups.

As used herein, “functional monomers or groups,” are monomer units inacrylic-based polymers which have reactive chemical groups which modifythe acrylic-based polymers directly or provide sites for furtherreactions. Examples of functional groups include carboxyl, epoxy andhydroxy groups.

As used herein “non-functional acrylic-based polymer” is defined as anacrylic-based polymer that has no or substantially no functionalreactive moieties present in the acrylic. These are generally acrylicesters which can be copolymerized with other monomers which do not havefunctional groups, such as vinyl acetate.

The term “carrier” as used herein refers to any non-aqueous materialknown in the art as suitable for transdermal drug deliveryadministration, and includes any polymeric material into which an activeagent may be solubilized in combination or admixture with the otheringredients of the composition. The polymeric materials preferablycomprise adhesives and, in particular, pressure-sensitive adhesives. Thecarrier material is typically used in an amount of about 40% to about90%, and preferably from about 50% to about 80%, by weight based on thedry weight of the total carrier composition.

The term “carrier composition” may also refer to enhancers, solvents,co-solvents and other types of addictives useful for facilitatingtransdermal drug delivery.

The carrier compositions of the present invention can also contain oneor more non-aqueous solvents and/or co-solvents. Such solvents and/orco-solvents are those known in the art, and are non-toxic,pharmaceutically acceptable substances, preferably non-aqueous liquids,which do not substantially negatively affect the adhesive properties orthe solubility of the active agents at the concentrations used. Thesolvent and/or co-solvent can be for the active agent or for the carriermaterials, or both.

Suitable solvents include volatile processing liquids such as alcohols(e.g., methyl, ethyl, isopropyl alcohols and methylene chloride);ketones (e.g., acetone); aromatic hydrocarbons such as benzenederivatives (e.g., xylenes and toluenes); lower molecular weight alkanesand cycloalkanes (e.g., hexanes, heptanes and cyclohexanes); andalkanoic acid esters (e.g., ethyl acetate, n-propyl acetate, isobutylacetate, n-butyl acetate isobutyl isobutyrate, hexyl acetate,2-ethylhexyl acetate or butyl acetate); and combinations and mixturesthereof. Other suitable co-solvents include polyhydric alcohols, whichinclude glycols, triols and polyols such as ethylene glycol, diethyleneglycol, propylene glycol, dipropylene glycol, trimethylene glycol,butylene glycol, polyethylene glycol, hexylene glycol, polyoxethylene,glycerin, trimethylpropane, sorbitol, polyvinylpyrrolidone, and thelike. Alternatively, co-solvents may include glycol ethers such asethylene glycol monoethyl ether, glycol esters, glycol ether esters suchas ethylene glycol monoethyl ether acetate and ethylene glycoldiacetate; saturated and unsaturated fatty acids, mineral oil, siliconefluid, lecithin, retinol derivatives and the like, and ethers, estersand alcohols of fatty acids. As will be described in more detailhereafter, the solvents or co-solvents used in accordance with theinvention are desirably a low volatile solvent that does not requireexcessive temperatures for evaporation thereof.

The term “solubilized” is intended to mean that in the carriercomposition there is an intimate dispersion or dissolution of the activeagent at the crystalline, molecular or ionic level, such that crystalsof the active agent cannot be detected using a microscope having amagnification of 25×. As such, the active agent is considered herein tobe in “non-crystallized” form when in the compositions of the presentinvention.

As used herein “flux” is defined as the percutaneous absorption of drugsthrough the skin, and is described by Fick's first law of diffusion:J==−D(dCm/dx),where J is the flux in g/cm²/sec, D is the diffusion coefficient of thedrug through the skin in cm²/sec and dCm/dx is the concentrationgradient of the active agent across the skin or mucosa.

As used herein, “therapeutically effective” means an amount of an activeagent that is sufficient to achieve the desired local or systemic effector result, such as to prevent, cure, diagnose, mitigate or treat adisease or condition, when applied topically over the duration ofintended use. The amounts necessary are known in the literature or maybe determined by methods known in the art, but typically range fromabout 0.1 mg to about 20,000 mg, and preferably from about 0.1 mg toabout 1,000 mg, and most preferably from about 0.1 to about 500 mg perhuman adult or mammal of about 75 kg body weight per 24 hours.

The term “about”, and the use of ranges in general whether or notqualified by the term about, means that the number comprehended is notlimited to the exact number set forth herein, and is intended to referto ranges substantially within the quoted range not departing from thescope of the invention.

The term “user” or “subject” is intended to include all warm-bloodedmammals, preferably humans.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the invention pertains. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice for testing of the present invention, the preferredmaterials and methods are described herein.

Referring to FIG. 1, the most preferred embodiment of the invention,transdermal drug delivery system 10 comprises a carrier compositionlayer 12 incorporating the active agent. Surface 14 of the adhesivecarrier layer 12 is affixed to release liner 15 to protect the carrierlayer prior to use but which is removed upon topical application of thecarrier layer to the skin or mucosa of the user. A non-drug containingpolymeric and/or adhesive coating 18 is affixed to backing 20 on onesurface, with the other surface being affixed to carrier layer 12.Backing composite 16 comprises coating 18 affixed to backing 20, whichas described later, is made or processed separately from carrier layer12 affixed to release liner 15.

Carrier composition layer 12 can comprise any polymer or adhesivegenerally known in the art for formulating a drug carrier composition,and include all of the non-toxic natural and synthetic polymers known orsuitable for use in transdermal systems including solvent-based, hotmelt and grafted adhesives, and may be used alone or in combinations,mixtures or blends. Examples include acrylic-based, silicone-based,rubbers, gums, polyisobutylenes, polyvinylethers, polyurethanes, styreneblock copolymers, styrene/butadiene polymers, polyether block amidecopolymers, ethylene/vinyl acetate copolymers, and vinyl acetate basedadhesives, and bioadhesives set forth in U.S. Pat. No. 6,562,363 whichis expressly incorporated by reference in its entirety.

The term “silicone-based” polymer is intended to be used interchangeablywith the terms siloxane, polysiloxane, and silicones as used herein andas known in the art. The silicone-based polymer may also be apressure-sensitive adhesive, with a polysiloxane adhesive prepared bycross-linking an elastomer, typically a high molecular weightpolydiorganosiloxane, with a resin, to produce a three-dimensionalsiloxane structure, via a condensation reaction in an appropriateorganic solvent. The ratio of resin to elastomer is a critical factorthat can be adjusted in order to modify the physical properties ofpolysiloxane adhesives. Sobieski, et al., “Silicone Pressure SensitiveAdhesives,” Handbook of Pressure-Sensitive Adhesive Technology. 2nd ed.,pp. 508-517 (D. Satas, ed.), Van Nostrand Reinhold, New York (1989).Further details and examples of silicone pressure-sensitive adhesiveswhich are useful in the practice of this invention are described in thefollowing U.S. Pat. Nos. 4,591,622; 4,584,355; 4,585,836; and 4,655,767,all expressly incorporated by reference in their entireties. Suitablesilicone pressure-sensitive adhesives are commercially available andinclude the silicone adhesives sold under the trademarks BIO-PSA® by DowCorning Corporation, Medical Products, Midland, Mich. (such as -2685,-3027, -3122, -4101, -4102, -4203, -4301, -4302, -4303, -4401 -4403,-4501, -4503, -4602, -4603 and -4919). Capped silicones with high resincontent are preferred.

In the practice of the preferred embodiments of the invention, theacrylic-based polymer can be any of the homopolymers, copolymers,terpolymers, and the like of various acrylic acids. In such preferredembodiments, the acrylic-based polymer constitutes from about 2% toabout 95% of the total dry weight of the of the carrier composition, andpreferably from about 2% to about 90%, and more preferably from about 2%to about 85%, wherein the amount of the acrylic-based polymer isdependent on the amount and type of drug used.

The acrylic-based polymers usable in the invention are polymers of oneor more monomers of acrylic acids and other copolymerizable monomers.The acrylate polymers also include copolymers of alkyl acrylates and/ormethacrylates and/or copolymerizable secondary monomers or monomers withfunctional groups. By varying the amount of each type of monomer added,the cohesive properties of the resulting acrylate polymer can be changedas is known in the art. In general, the acrylate polymer is composed ofat least 50% by weight of an acrylate or alkyl acrylate monomer, from 0to 20% of a functional monomer copolymerizable with the acrylate, andfrom 0 to 40% of other monomers.

Acrylate monomers which can be used include acrylic acid, methacrylicacid, butyl acrylate, butyl methacrylate, hexyl acrylate, hexylmethacrylate, 2-ethylbutyl acrylate, 2-ethylbutyl methacrylate, isooctylacrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexylmethacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate,dodecyl methacrylate, tridecyl acrylate, and tridecyl methacrylate.

Functional monomers, copolymerizable with the above alkyl acrylates ormethacrylates, which can be used include acrylic acid, methacrylic acid,maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropylacrylate, acrylamide, dimethylacrylamide, acrylonitrile,dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate,tert-butylaminoethyl acrylate, tert-butylaminoethyl methacrylate,methoxyethyl acrylate and methoxyethyl methacrylate.

Suitable acrylic-based polymers may also be a pressure-sensitiveadhesive which are commercially available and include the acrylic-basedadhesives sold under the trademarks Duro-Tak® by National Starch andChemical Corporation, Bridgewater, N.J. (such as 87-2287, -4098, -2852,-2196, -2296, -2194, -2516, -2070, -2353, -2154, -2510, -9085 and-9088). Other suitable acrylic-based adhesives include HRJ 4483, 10127,and 11588 sold by Schenectady International, Inc., Schenectady, N.Y.,and those sold by Monsanto; St. Louis, Mo., under the trademarks Gelva®Multipolymer Solution (such as 2480, 788, 737, 263, 1430, 1753, 1151,2450, 2495, 3067, 3071, 3087 and 3235.

The carrier composition may comprise blends of acrylic-based polymers,silicone-based polymers and rubbers based upon their differingsolubility parameters, alone or in combination with other polymers, forexample polyvinylpyrrolidone, as more fully described in U.S. Pat. Nos.5,474,783; 5,656,286; 5,958,446; 6,024,976; 6,221,383; and 6,235,306which are incorporated herein in their entirety. The amount of eachpolymer is selected to adjust the saturation concentration of the drugin the multiple polymer system, and to result in the desired rate ofdelivery of the drug from the system and through the skin or mucosa.

Combinations of acrylic-based polymers based on their functional groupsis also contemplated. Acrylic-based polymers having functional groupsare copolymers or terpolymers which contain in addition to nonfunctionalmonomer units, further monomer units having free functional groups. Themonomers can be monofunctional or polyfunctional. These functionalgroups include carboxyl groups, hydroxy groups, amino groups, amidogroups, epoxy groups, etc. Preferred functional groups are carboxylgroups and hydroxy groups. Preferred carboxyl functional monomersinclude acrylic acid, methacrylic acid, itaconic acid, maleic acid, andcrotonic acid. Preferred hydroxy functional monomers include2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylate, hydroxymethylacrylate, hydroxymethyl methacrylate, hydroxyethyl acrylate,hydroxyethyl methacrylate, hydroxypropyl acrylate, hydroxypropylmethacrylate, hydroxybutyl acrylate, hydroxybutyl methacrylate,hydroxyamyl acrylate, hydroxyamyl methacrylate, hydroxyhexyl acrylate,hydroxyhexyl methacrylate. Non-functional acrylic-based polymers caninclude any acrylic based polymer having no or substantially no freefunctional groups. The acrylic based polymer can include homopolymers,copolymers and terpolymers. The monomers used to produce the polymerscan include alkyl acrylic or methacrylic esters such as methyl acrylate,ethyl acrylate, propyl acrylate, amyl acrylate, butyl acrylate,2-ethylbutyl acrylate, hexyl acrylate, heptyl acrylate, octyl acrylate,nonyl acrylate, 2-ethylhexyl acrylate, decyl acrylate, dodecyl acrylate,tridecyl acrylate, glycidyl acrylate and the corresponding methacrylicesters.

Both the acrylic-based polymer having substantially no functional groupsand acrylic-based polymers having functional groups can optionallyinclude further modifying monomers. These modifying monomers can includeany conceivable monomer that is capable of undergoing vinylpolymerization. For example, the incorporation of styrene monomers canbe used to increase the glass transition temperature and are sometimesused to improve the cohesive strength. The copolymerization of vinylacetate monomers with acrylic esters are also used to form acrylic-basedpolymers. Ethylene can also be copolymerized with acrylic esters andvinyl acetate to give suitable acrylic-based polymers.

For example, a composition will require less of a functional acrylicthat contains 20% by weight of functional groups as opposed to one thatcontains 0.5% by weight of functional groups to achieve the same effectrequired for solubility and flux. Broadly speaking, the amount offunctional acrylic is generally within the range of about 1 to 99 weight% and preferably 5 to 95 weight %, more preferably 20 to 75 weight %,even more preferably 30 to 65 weight %, based on the total polymercontent of the transdermal composition. The amount of non-functionalacrylic or acrylic with a functional group which does not have as greatof an affinity for the drug, is within the range of about 99 to 1 weight%, preferably 95 to 5 weight %, more preferably 75 to 20 weight % andeven more preferably 30 to 65 weight %, based on the total polymercontent of the composition.

Further details and examples of acrylic-based adhesives, functionalmonomers, and polymers which have no functional groups and which aresuitable in the practice of the invention are described in Satas,“Acrylic Adhesives,” Handbook of Pressure-Sensitive Adhesive Technology,2nd ed., pp. 396-456 (D. Satas, ed.), Van Nostrand Reinhold, N.Y.(1989); “Acrylic and Methacrylic Ester Polymers,” Polymer Science andEngineering, Vol. 1, 2nd ed., pp 234-268, John Wiley & Sons, (1984);U.S. Pat. No. 4,390,520; and U.S. Pat. No. 4,994,267 all of which areexpressly incorporated by reference in their entireties.

The required proportions of acrylic-based or other polymers used aregenerally dependant on the specific drug, its desired delivery rate andthe desired duration of drug delivery. In general, proportions ofacrylic-based polymers also depend on the content of the functionalmonomer units in the functional acrylic.

When the drug carrier composition is intended to function as the facelayer, that is the layer that comes in contact with the topical site ofapplication as depicted in FIG. 1, it is preferable that the carriercomposition comprise a pressure-sensitive adhesive or bioadhesive.

In transdermal systems according to the invention, the drug carriercomposition is designed to minimize or prevent the loss of drug and/orother desirable volatile components, such as hydrophillic permeationenhancers, in compositions containing processing solvents, as well asprovide selectable modulation of delivery rates, onset and profiles ofthe drug when used in combination with a non-drug containing polymericand/or adhesive coating that is applied to either the transdermalsystem's backing or release liner.

Minimizing or preventing drug loss is particularly desirable when tryingto deliver controlled substances. With drugs that have relatively lowboiling or melting points, such as drugs that are liquid at or near roomtemperature, or are easily volatilized and/or degraded during themanufacture of the transdermal delivery system one can experience drugloss during processing. This is particularly relevant for controlledsubstances for which regulatory agencies, such as the FDA, requireaccountability for any loss of the controlled substance. Particulardrugs that are usable in the present invention include low molecularweight drugs. Any drug which is liquid at or about room temperature canbe used according to the present invention. As used herein, the term“low molecular weight” is defined to include any drug and its equivalentforms that has a melting point such that it exists as a liquid at orabout room temperatures. This term encompasses low molecular weightdrugs having a molecular weight of less than about 300 daltons. A drugwhich is of low molecular weight and liquid at or about roomtemperatures is generally in its free-base or free-acid form, and, assuch, is encompassed by this term. Drugs usable in practicing theinvention include amphetamine, d-amphetamine, methaphetame, prilocaine,benzocaine, butacaine, butamben, butanilicaine, corticaine, lidocaine,memantine, pilocarpine, cyclobenzaprine, paroxetine, fluoxetine,duloxetine, imipramine, decipramine, doxeprin, nortriptylene,protriptylene, bupropion, azelastine, chlorphenamine, bisoprolol,pheniramine, alprazolam, captopril, clonidine, clonazepam, enalapril,ramipril, haloperidol, ketoprofen, loratadine, methimazole(anti-hyperthyroid), methylphenidate, methyl testosterone, nicotine,nitroglycerin, pramipexole, ropinirole, hydromorphone, selegiline(deprenyl and L-deprenyl), scopolamine, testosterone, methamphetamine,and phentermine. For desired therapeutic effect, it may be desirablecertain drugs, such as methylphenidate, d-amphetamine, methamphetamineand phentermine, be used in their base form. Transdermal delivery ofd-amphetamine base is preferably used to treat Attention Deficit andHyperactivity disorders, and appetite suppression. Transdermal deliveryof a combination of d-amphetamine base and l-amphetamine base ispreferably used to treat Attention Deficit and Hyperactivity disorders,and appetite suppression. Transdermal delivery of a combination ofd-amphetamine base and l-amphetamine base is preferably used to treatAttention Deficit and Hyperactivity disorders, and appetite suppressionwherein the d to l ratio of the amphetamine base is between about 1 to 1to about 4 to 1. Transdermal delivery of a combination of d-amphetaminebase and 1-amphetamine base is preferably used to treat AttentionDeficit and Hyperactivity disorders, and appetite suppression whereinthe d to 1 ratio of the amphetamine base is between about 3 to 1 toabout 4 to 1.

Any molecular weight drug and its equivalent forms can be used in thepresent invention as long as such drugs would be substantially unstableor be substantially evaporated or driven-off at the temperaturesgenerally known or used in the art to remove solvents during themanufacturing processing, typically in the range of 160° F. to 250° F.,by their own properties or by virtue of their relative volatility orreactivity with the other carrier components. In certain otherembodiments, the preferred drug is one that is hydrophillic and notrelatively volatile or reactive with the other carrier components, butwhich is incorporated into a carrier composition with certainco-solvents or enhancers preferred for use with such drugs that wouldbe, by their own properties or by virtue of their relative volatility orreactivity with the other carrier components, substantially unstable orsubstantially evaporated or driven-off at the temperatures generallyknown or used in the art to remove solvents during the manufacturingprocessing.

The drugs and mixtures thereof can be present in the composition indifferent forms, depending on which yields the optimum deliverycharacteristics. Thus, the drug can be in its free base form or in theform of salts, esters, or any other pharmacologically acceptablederivatives, or as prodrugs, components of molecular complexes or ascombinations of these.

Any drug suitable for transdermal administration by methods previouslyknown in the art and by the methods of the present invention can be usedin the present invention, and further include such active agents thatmay be later established as drugs and are suitable for delivery by thepresent invention. These drugs include but are not limited to thosecategories and species of drugs set forth on page ther-1 to ther-28 ofthe Merck Index, 12th Edition Merck and Co. Rahway, N.J. (1999). Thisreference is incorporated by reference in its entirety. Exemplary ofdrugs that can be administered by the novel dermal drug delivery systeminclude, but are not limited to:

1. Central nervous system stimulants and agents such asDextroamphetamine, Amphetamine, Methamphetamine, D-Amphetamine,L-amphetamine Phentermine, Methylphenidate, Nicotine combinationsthereof and combinations thereof.

2. Analgesics and/or Anti-Migraine such as Acetaminophen,Acetylsalicylic Acid, Buprenorphine, Codeine, Fentanyl, Lisuride,Salicylic Acid derivatives and Sumatriptan.

3. Androgen agents such as Fluoxymesterone, Methyl Testosterone,Oxymesterone, Oxymetholone, Testosterone and Testosterone derivatives.

4. Anesthetic agents such as Benzocaine, Bupivicaine, Cocaine,Dibucaine, Dyclonine, Etidocaine, Lidocaine, Mepivacaine, Prilocaine,Procaine and Tetracaine.

5. Anoretic agents such as Fenfluramine, Mazindol and Phentermine.

6. Anti-Bacterial (antibiotic) agents including Aminoglycosides,β-Lactams, Cephamycins, Macrolides, Penicillins, Polypeptides andTetracyclines.

7. Anti-Cancer agents such as Aminolevulinic Acid and Tamoxifen.

8. Anti-Cholinergic agents such as Atropine, Eucatropine andScopolamine.

9. Anti-Diabetic agents such as Glipizide, Glyburide, Glypinamide andInsulins.

10. Anti-Fungal agents such as Clortrimazole, Ketoconazole, Miconazole,Nystatin and Triacetin.

11. Anti-Inflammatory and/or Corticoid agents such as Beclomethasone,Betamethasone, Betamethasone Diproprionate, Betamethasone Valerate,Corticosterone, Cortisone, Deoxycortocosterone and Deoxycortocosterone,Acetate, Diclofenac, Fenoprofen, Flucinolone, Fludrocortisone,Fluocinonide, Fluradrenolide, Flurbiprofen, Halcinonide, Hydrocortisone,Ibuprofen, Ibuproxam, Indoprofen, Ketoprofen, Ketorolac, Naproxen,Oxametacine, Oxyphenbutazone, Piroxicam, Prednisolone, Prednisone,Suprofen and Triamcinolone Acetonide.

12. Anti-Malarial agents such as Pyrimethamine.

13. Anti-Parkinson's and/or Anti-Alzhiemer's agents such asBromocriptine, 1-Hydroxy-Tacrine, Levodopa, Lisaride Pergolide,Pramipexole, Ropinirole, Physostigimine, Selegiline (Deprenyl andL-Deprenyl), Tacrine Hydrochloride and Teruride.

14. Anti-Psychotic and/or Anti-Anxiety agents such as Acetophenazine,Azapirones, Bromperidol, Chlorproethazine, Chlorpromazine, Fluoxetine,Fluphenazine, Haloperidol, Loxapine, Mesoridazine, Molindone,Ondansetron, Perphenazine, Piperacetazine, Thiopropazate, Thioridazine,Thiothixene, Trifluoperazine and Triflupromazine.

15. Anti-Ulcerative agents such as Enprostil and Misoprostol.

16. Anti-Viral agents such as Acyclovir, Rimantadine and Vidarabine.

17. Anxiolytic agents such as Buspirone, Benzodiazepines such asAlprazolam, Chlordiazepoxide, Clonazepam, Clorazepate, Diazepam,Flurazepam, Halazepam, Lorazepam, Oxazepam, Oxazolam, Prazepam andTriazolam.

18. β-Adrenergic agonist agents such as Albuterol, Carbuterol,Fenoterol, Metaproterenol, Rimiterol, Quinterenol, Salmefamol,Soterenol, Tratoquinol, Terbutaline and Terbuterol.

19. Bronchodilators such as Ephedrine derivatives including Epiniphrineand Isoproterenol, and Theophylline.

20. Cardioactive agents such as Atenolol, Benzydroflumethiazide,Bendroflumethiazide, Calcitonin, Captopril, Chlorothiazide, Clonidine,Dobutamine, Dopamine, Diltiazem, Enalapril, Enalaprilat, Gallopamil,Indomethacin, Isosorbide Dinitrate and Mononitate, Nicardipine,Nifedipine, Nitroglycerin, Papaverine, Prazosin, Procainamide,Propranolol, Prostaglandin E₁, Quinidine Sulfate, Timolol, andVerapamil.

21. α-Adrenergic agonist agents such as Phenylpropanolamine.

22. Cholinergic agents such as Acetylcholine, Arecoline, Bethanechol,Carbachol, Choline, Methacoline, Muscarine and Pilocarpine.

23. Estrogens such as Conjugated Estrogenic Hormones, Equilenin,Equilin, Esterified Estrogens, 17β-Estradiol, Estradiol Benzoate,17β-Estradiol Valerate, Estradiol 17β-Cypionate, Estriol, Estrone,Estropipate, 17β-Ethinyl Estradiol and Mestranol.

24. Muscle relaxants such as Baclofen.

25. Narcotic antagonist agents such Nalmfene and Naloxone.

26. Progestational agents such as Chlormadinone and ChlormadinoneAcetate, Demegestone, Desogestrel, Dimethisterone, Dydrogesterone,Ethinylestrenol, Ethisterone, Ethynodiol and Ethynodiol Diacetate,Gestodene, 17α-Hydroxyprogesterone, Hydroxygesterone Caproate,Medroxyprogesterone and Medroxyprogesterone Acetate, Megestrol Acetate,Melengestrol, Norethindrone and Norethidrone Acetate, Norethynodrel,Norgesterone, Norgestrel, 19-Norprogesterone, Progesterone, Promegestoneand esters thereof. Free base forms of drugs which have a greateraffinity for the acid (carboxyl) functional group in a carboxylfunctional acrylic-based polymer are preferred in some applications.

For most drugs, their passage through the skin or mucosa will be therate-limiting step in delivery. Thus, the amount of drug and the rate ofrelease is typically selected so as to provide delivery characterized bya pseudo-zero order time dependency for a prolonged period of time. Theminimum amount of drug in the system is selected based on the amount ofdrug which passes through the skin or mucosa in the time span for whichthe device is to provide a therapeutically effective amount. Generally,the amount of drug in the transdermal system can vary from about 0.1 to40% by weight, preferably 0.5 to 30% by weight, and optimally 1-20%weight per cent, based on the total dry weight of the agent-carriercomposition.

In the preferred embodiments of the invention, the inventors have foundthat by preparing and processing the drug carrier composition andpolymeric coating separately, greater flexibility is afforded whenmanufacturing a transdermal device employing processing solvents orsolvent-based adhesives. Such solvents are typically volatile,non-aqueous liquids, and are used to solubilize or dissolve the activeagent and polymers together into a composition that can more easily beprocessed into a transdermal system, such as by coating or casting.Typical liquids are volatile polar and non-polar organic liquids such aslower molecular weight alkanols (e.g., isopropanol and ethanol),aromatics such as benzene derivatives (e.g., xylene and toluene), lowermolecular weight alkanes and cycloalkanes (e.g., hexane, heptane andcyclohexane) and alkanoic acid esters such as ethyl or butyl acetate.Such solvents are sometimes added to the carrier composition (alsoreferred to as co-solvents) and are typically found in the commerciallyavailable adhesives as is known in the art to prepare transdermalsystems. The drug carrier composition should be substantially free ofresidual solvents after manufacture, preferably less than 0.5% and morepreferably 0.2% or less.

To minimize loss of the desirable components while making a transdermalsystem in accordance with the invention, the amount of processingsolvents typically needed to solubilize the drug or polymer into adesirable composition (and achieve the other design and performancecharacteristics for a transdermal system) is minimized or substantiallyreduced. In this respect, the drug carrier composition can be preparedwith a greater amount of solids versus solvents, and still manufacturedin a simple and cost-effective manner. By increasing the solids content,a relatively low amount of volatile solvent, such as an ethyl acetate,can be used. This will greatly reduce drying times and the need tosubject the carrier composition to elevated temperatures, and thereforeminimize the chance of loss of desired volatile components, such as thedrug. This in turn results in a carrier composition wherein the amountof drug necessary to achieve the desired permeation rate and profile canbe significantly reduced from what would otherwise be needed, or beimpossible to adequately load, as the loss of such drug is minimized.

With respect to acrylics and silicones, this refers to their monomericor resin/polymer content, respectively. Typical carrier compositionslimit their overall solids content to about 40% to 50% as it isdesirable or necessary to provide sufficient solvents to solubilize asufficient amount of the active agent and/or solids therein, and stillimpart sufficient adhesive and cohesive properties to form a transdermaldelivery system. However, such compositions require a significant amountof solvent to be removed. The agent carrier according to the inventionis therefore prepared with a solids content from about 50% to 98% of thetotal weight of the carrier composition, or more preferably in the rangeof about 65% to about 85%.

In preferred embodiments using both acrylic and silicone adhesives, thesolids content and amount of the silicone-based adhesive can beincreased to about 70% to about 80%, and 60% to about 80% weightpercent, respectively, while the amount of acrylic adhesive can bereduced to about 1% to about 15% weight percent based on the dry weightof the total carrier composition. Use of an acrylic adhesive as part ofthe carrier composition is preferred, particularly with siliconeadhesives, because of its ability to solubilize and hold onto drug andstill impart adhesive properties for attachment to other transdermalfilms/layers and skin or mucosa. Such acrylic adhesives should notexceed a percent solids amount of greater than about 40% when used inthe lower ranges described to retain their desired effect. When usedalone or in blends, the percent solids of such acrylic adhesives wouldneed to be substantially increased.

The amount of drug typically lost during processing to remove solventsfrom a carrier composition can be as high as 20%, and even 40% or more,depending on the functionality or capping of the adhesives or by virtueof the drug's relative volatility or reactivity with the other carriercomponents. Due to the relatively thick coating weights of carriercompositions needed to provide the necessary amount of drug andadhesive/cohesive properties to achieve the desired final product whendried, the manufacturing process required relatively prolonged exposureto elevated temperatures to substantially remove the solvents. A furtherbenefit of the invention is the ability to increase processing speedsduring manufacturing, since the coat weight of the carrier compositionand/or the concentration of the drug can be reduced. For example,typical carrier compositions prepared with acrylic-based polymers orblend of polymers for a transdermal delivery device require coat weightsof about 10 mg/cm² to achieve the desired drug loading and adhesivecharacteristics. In the present invention, the coat weight of a carriercomposition for delivering at least one drug at a similar flux may bereduced to about 5 mg/cm², or about one-half the coat weight of priorsystems.

The agent-carrier composition according to the invention, containingsignificantly higher solids content and lower solvents, and capable ofbeing coated to a backing or release liner at a lower coat weight, canbe processed faster or with reduced exposure to elevated temperatures inorder to minimize or prevent loss of drug or other desirable components,such as hydrophillic enhancers, but it cannot still achieve othernecessary design and performance characteristics to be a transdermaldelivery device. Increasing per cent solids increases the “stiffness” ofthe carrier which can adversely affect the adhesive and cohesiveproperties required to function as a pressure-sensitive adhesive fortopical application. Additionally, increasing per cent solids candecrease the ability of the carrier to adequately solubilize and holdonto the drug which further adversely affects pressure-sensitiveproperties as well as a controlled delivery rate or profile.

Accordingly, the carrier composition of the invention cannot adequatelyprovide a controlled delivery, onset or profile for the drug, or theneeded adhesive and cohesive properties, to be used by itself as atransdermal device until combined with a non-drug loaded polymericand/or adhesive coating that is applied to either the backing or therelease liner.

The polymeric coating 18 may comprise one or more of the polymers oradhesives described with reference to the drug carrier composition,generally with higher per cent solids, but contain no active agentduring its exposure to elevated temperatures for solvent removal priorto being affixed to the drug carrier composition. Preferred arenon-functional, acrylic-based adhesives. The polymeric coating isdisposed on either the backing or release liner and generally at athickness ranging from about 2.5 mg/cm² to about 15 mg/cm².

Once affixed to the carrier composition, it serves to absorb or attractand retain amounts of drug from the drug carrier composition, andsubsequently release drug upon topical application of the transdermalsystem. This process further allows for potentially higher drug loadingin the carrier composition, where desired or needed, for example todeliver therapeutically effective amounts over a longer period ofdelivery, since excess drug will be absorbed away thereby permitting thecarrier composition to maintain its desired adhesive properties whilestill providing desired permeation rate and profile to be achieved.

The polymeric coating can further be prepared to selectively control thedesired delivery rate, onset and profile for the drug by varying certainother physical characteristics. As demonstrated in the examplesemploying an acrylic-based adhesive coating, the delivery rate, onset ofdelivery (lag time) and delivery profile of amphetamine base from thetransdermal system may be selectively modulated by one or more of (a)increasing or decreasing the thickness or coat weight of per cm² (asapplied to the backing or release liner of the system), (b) manipulatingthe moiety or functionality, and (c) manipulating the monomericcomposition an/or ratios, of the acrylic-based non-drug loaded coating.

While one or more acrylic-based adhesives are preferred for use as thenon-drug loaded coating, other polymers, alone or in combination, may beused provided such polymers have the ability to (a) incorporate and holddrug from the drug-loaded carrier composition after manufacture, (b)maintain contact/adhesion to both the carrier composition and either thebacking film/layer or the release liner, preferably without the use ofadditional adhesives, (c) not degrade or interfere with stability of thedrug, and (d) release or deliver the drug to the skin or mucosa aftertopical application of the transdermal system.

In the most preferred embodiment according to the invention as depictedin FIG. 1, about 10% to about 30%, and more preferably from about 10% toabout 20% drug, and more particularly amphetamine or an enantiomerthereof, d-amphetamine preferred, or in a racemic mixture, 3:1 d- tol-preferred, is incorporated into a pressure-sensitive adhesive carriercomposition comprising a blend of (a) a solvent-based acrylic adhesivehaving a per cent solids concentration of about 30% to 50%, preferablypolymerized with non-functional monomers, in an amount from about 60% to80%, and more preferably from about 70% to about 80% and (b) asilicone-based adhesive having a per cent solids concentration of about60% to about 90%, and more preferably from about 60% to about 80%, thatis affixed to a non-drug acrlylic coating that is an adhesive and has aper cent solids concentration of about 30% to about 50%, preferablypolymerized with non-functional and/or carboxy functional monomers, inan amount from about 3% to about 15%, and more preferably from about 3%to about 10%, wherein the amounts described are based on the dry weightof the total carrier composition. Drug delivery is desired from such asystem at a rate of about 0.1 mg/cm² to about 10 mg/cm² and morepreferably 0.1 mg/cm² to about 0.6 mg/cm², to deliver from about 2 toabout 50 mg per 24 hours.

In certain embodiments of the invention, an enhancer can be incorporatedinto either the carrier composition or the polymeric coating, or both.The term “enhancers” as used herein refers to substances used toincrease permeability and/or accelerate the delivery of an active agentthrough the skin or mucosa, and include monhydric alcohols such asethyl, isopropyl, butyl and benzyl alcohols; or dihydric alcohols suchas ethylene glycol, diethylene glycol, or propylene glycol, dipropyleneglycol and trimethylene glycol; or polyhydric alcohols such as glycerin,sorbitol and polyethylene glycol, which enhance drug solubility;polyethylene glycol ethers of aliphatic alcohols (such as cetyl, lauryl,oleyl and stearly) including polyoxyethylene (4) lauryl ether,polyoxyethylene (2) oleyl ether and polyoxyethylene (10) oleyl ethercommercially available under the trademark BRIJ® 30, 93 and 97 from ICIAmericas, Inc., and BRIJ® 35, 52, 56, 58, 72, 76, 78, 92, 96, 700 and721; vegetable, animal and fish fats and oils such as cotton seed, corn,safflower, olive and castor oils, squalene, and lanolin; fatty acidesters such as propyl oleate, decyl oleate, isopropyl palmitate, glycolpalmitate, glycol laurate, dodecyl myristate, isopropyl myristate andglycol stearate which enhance drug diffusibility; fatty acid alcoholssuch as oleyl alcohol and its derivatives; fatty acid amides such asoleamide and its derivatives; urea and urea derivatives such asallantoin which affect the ability of keratin to retain moisture; polarsolvents such as dimethyldecylphosphoxide, methyloctylsulfoxide,dimethyllaurylamide, dodecylpyrrolidone, isosorbitol, dimethylacetonide,dimethylsulfoxide, decylmethylsulfoxide and dimethylformamide whichaffect keratin permeability; salicylic acid which softens the keratin;amino acids which are penetration assistants; benzyl nicotinate which isa hair follicle opener; and higher molecular weight aliphaticsurfactants such as lauryl sulfate salts which change the surface stateof the skin and drugs administered and esters of sorbitol and sorbitolanhydride such as polysorbate 20 commercially available under thetrademark Tween® 20 from ICI Americas, Inc., as well as otherpolysorbates such as 21, 40,60, 61, 65, 80, 81, and 85. Other suitableenhancers include oleic and linoleic acids, triacetin, ascorbic acid,panthenol, butylated hydroxytoluene, tocopherol, tocopherol acetate,tocopheryl linoleate. If enhancers are incorporated into the transdermalsystem, the amount typically ranges up to about 30%, and preferably fromabout 0.1% to about 15%, by weight based on the dry weight of the totalcarrier composition.

Enhancers preferred for use in the drug carrier composition andpolymeric coating differ by virtue of the their differing processingconditions. Enhancers suitable for use with the polymeric coating arethose with sufficiently high boiling points or lower volatile reactivitywithin the coating to withstand prolonged exposure to elevatedprocessing temperatures employed to drive off the solvents therein, andinclude monovalent, saturated and unsaturated aliphatic andcycloaliphatic alcohols having 6 to 12 carbon atoms such ascyclohexanol, lauryl alcohol and the like; aliphatic and cycloaliphatichydrocarbons such as mineral oils; cycloaliphatic and aromatic aldehydesand ketones such as cyclohexanone; N,N-di(lower alkyl)acetamides such asN,N-diethyl acetamide, N,N-dimethyl acetamide,N-(2-hydroxyethyl)acetamide, and the like; aliphatic and cycloaliphaticesters such as isopropyl myristate and lauricidin; N,N-di(loweralkyl)sulfoxides such as decylmethyl sulfoxide; essential oils; nitratedaliphatic and cycloaliphatic hydrocarbons such asN-methyl-2-Pyrrolidone, Azone; salicylates, polyalkylene glycolsilicates; aliphatic acids such as oleic acid and lauric acid, terpenessuch as cineole, surfactants such as sodium lauryl sulfate, siloxanessuch as hexamethyl siloxane; polyethylene glycols, polypropyleneglycols, and polyether polyols, epoxidized linseed oils, simple liquidesters, and the like, alone or in combination.

On the other hand, enhancers suitable for use with the drug carriercomposition are those with lower boiling points or higher relativevolatility or reactivity within the carrier composition since exposureto elevated processing temperatures is decreased, and therefore theirloss, similar to drug loss, is decreased. Such enhancers are well knownin the art and examples include alcohols, propylene glycol, dipropyleneglycol, butylene glycol, m-pyrol, oleates, and laurates, with propyleneglycol being preferred.

In addition to enhancers, there may also be incorporated variouspharmaceutically acceptable additives and excipients available to thoseskilled in the art. These additives include tackifying agents such asaliphatic hydrocarbons, mixed aliphatic and aromatic hydrocarbons,aromatic hydrocarbons, substituted aromatic hydrocarbons, hydrogenatedesters, polyterpenes, silicone fluid, mineral oil and hydrogenated woodrosins. Additional additives include binders such as lecithin which“bind” the other ingredients, or rheological agents (thickeners)containing silicone such as fumed silica, reagent grade sand,precipitated silica, amorphous silica, colloidal silicon dioxide, fusedsilica, silica gel, quartz and particulate siliceous materialscommercially available as Syloid®, Cabosil®, Aerosil®, and Whitelite®,for purposes of enhancing the uniform consistency or continuous phase ofthe composition or coating. Other additives and excipients includediluents, stabilizers, fillers, clays, buffering agents, biocides,humectants, anti-irritants, antioxidants, preservatives, plasticizingagents, cross-linking agents, flavoring agents, colorants, pigments andthe like. Such substances can be present in any amount sufficient toimpart the desired properties to the composition or coating. Suchadditives or excipients are typically used in amounts up to 25%, andpreferably from about 0.1% to about 10%, by weight based on the dryweight of the total carrier composition.

Transdermal system 10 further employs release liners orremovable/peelable covers and backings to protect and/or anchor thesystem or its components during manufacturing as described herein, orthereafter, and to enable handling and transportation.

The release liner is typically impermeable and occlusive, and must becompatible with the particular polymers or active agents so as not tointerfere with the composition's ultimate application and therapeuticeffect. Some suitable materials that can be used, singularly, incombination, as laminates, films, or as coextrusions, to form therelease liner are well known in the art. When the release liner iscomposed of a material which typically does not readily release (i.e.,is not easily removed or separated from the coating or composition towhich it is affixed), for example paper, a releasable material such as asilicone, Teflon®, or the like may be applied to the surface by anyconventional means. Preferred release liners are films commerciallyavailable from DuPont, Wilmington, Del., under the trademarks Mylar®,and fluropolymer (silicone) coated films commercially available fromRexam Release, Oak Brook, Ill. under the trademarks FL2000® andMRL2000®, and from 3M Corporation, St. Paul, Minn. Sold under thetrademarks ScotchPak® such as 1022.

The backing is typically moisture impermeable and flexible but should becompatible with the particular polymers or active agents used so as notto interfere with the composition's ultimate application and therapeuticeffect. Some suitable materials that can be used, singularly, incombination, as laminates, films or as coextrusions, to form the backinglayer 20 are also well known in the art and include films or sheets ofpolyethylene, polyester, polypropylene, polyurethane, polyolefin,polyvinyl alcohol, polyvinyl chloride, polyvinylidene, polyamide, vinylacetate resins, BAREX®, ethylene/vinyl acetate copolymers,ethylene/ethylacrylate copolymers, metal-vapor deposited films or sheetsthereof, rubber sheets or films, expanded synthetic resin sheets orfilms, non-woven fabrics, fabrics, knitted fabrics, clothes, foils andpapers. The backing layer 20 may generally have a thickness in the rangeof 2 to 1000 micrometers. The backing layer 20 may be pigmented, forexample colored to either match with or conversely easily distinguishfrom the site of application, and/or contain printing, labeling andother means of identification and/or traceability of the transdermalunit or system itself. The backing layer 20 may further be made opaqueor substantially opaque (i.e., preventing light or certain energywavelengths from penetrating or passing through), such as bymetallization, fillers, inks, dyes and the like, for purposes ofprotecting photosensitive active agents from degradation and/orpreventing photoallergic reactions or irritations on the subject.

In the manufacture of a transdermal system 10 according to the presentinvention, drug carrier composition 12 and the non-drug loaded polymericand/or adhesive coating 18 are prepared separately and then combined.The drug carrier and polymeric coating comprising the present inventioncan be prepared in any manner known to those of skill in the art.

An exemplary general method of preparing transdermal system 10 is asfollows:

1. Appropriate amounts of the polymer(s), adhesive(s), solvent(s),co-solvent(s), enhancer(s), additive(s) and/or excipient(s) are combinedand thoroughly and uniformly mixed together in a vessel to form thenon-drug loaded polymeric coating.

2. The polymeric coating is then transferred to a coating operationwhere it is cast onto a backing film/layer at a controlled specifiedthickness and exposed to elevated temperatures, such as in an oven, toremove the volatile processing solvents.

3. The polymeric coating is then laminated to a release liner applied tothe surface opposite the backing/layer and wound into rolls.

4. Appropriate amounts of drug(s), polymer(s), adhesive(s), solvent(s),co-solvent(s), enhancer(s), additive(s) and/or excipient(s) are combinedand thoroughly and uniformly mixed together in a vessel to form theactive agent carrier composition.

5. The composition is then transferred to a coating operation where itis cast onto a release liner at a controlled specified thickness andexposed to elevated temperatures, such as in an oven, to remove thevolatile processing solvents.

6. As depicted in FIG. 2, the release liner 22 that is affixed to thepolymeric coating 18 to form the backing composite 16 is then removedand affixed to the exposed surface of the drug carrier composition 12,and the laminated assembly is wound into rolls.

7. Thereafter, desired size and shape delivery systems 10 are preparedby die-cutting or the like, from the rolled laminate and then packaged.

Alternatively, the release liner 22 may not be necessary if both theagent-carrier composition 12 and backing composite 16 are producedconcomitantly, wherein attachment to each other could be performed afterprocessing of each individually, such as in an in-line process, therebyavoiding step 3 above. As described earlier, either the drug carriercomposition 12 or the polymeric coating 18 may be an adhesive orpressure-sensitive adhesive, allowing pressure lamination to each otherby their adhesive qualities. However, where a release liner 22 isemployed in the manufacturing steps, it is preferable to affix it to thepolymeric coating and not the drug carrier composition to prevent anyfurther drug loss that could occur from winding into rolls andsubsequent removal of such release liner, or the failure of releaseliner 22 to adhere to the drug carrier composition.

Additionally and alternatively, a separate adhesive may be used to (a)affix the backing composite 16 to the drug carrier composition 12 at thesurface opposite the release liner 15 and/or (b) affix the polymericcoating or the drug carrier composition, depending on which is to beused as the point of topical application to the skin or mucosa, toeither the backing film/layer or the release liner.

In certain other preferred embodiments, a non-woven drug permeablefilm/layer, such as a polyester film, may be interdisposed, such aspressure lamination, for structural support or ease of manufacturing(i.e., has no effect on controlling drug permeation or delivery) betweenthe non-drug loaded coating and the drug-loaded carrier composition.

When manufacturing a transdermal system to deliver certain drugs, suchas amphetamine base, that are volatilized at or near ambienttemperatures and/or degraded by exposure to atmospheric air, or thatemploy use of volatile enhancers, particular care should be employed toavoid prolonged processing times or exposure to air. In this regard,controlled manufacturing environments, for example employing lowertemperatures or pressures, modifying atmospheric gases present (suchreduced carbon dioxide levels or using nitrogen in place of air), ormodifying air or gas flow (such as during oven drying to removesolvents) at various stages during the process, may also be necessary ordesirable.

The order of the processing steps, the amount of the ingredients, andthe amount and time of agitation or mixing may be important processvariables which will depend on the specific polymers, active agents,solvents or co-solvents, enhancers and additives and excipients used inthe transdermal system. These factors can be adjusted by those skilledin the art, while keeping in mind the objects of achieving theinteraction between the drug carrier composition and the non-drug loadedcoating. It is believed that a number of other methods, for example,other methods of coating that are well-known in the art, such as Mayerrod, gravure, knife-over roll, extrusion, casting, calendaring andmolding, or changing the order of certain steps, can be carried out andwill also give desirable results.

EXAMPLES

In the Examples as shown with respect to FIGS. 3-5, the effect ofvariations in the non-drug loaded coating are determined, indicating theeffective control of permeation rate, onset and profile thereby.Referring to the most preferred embodiment depicted in FIG. 1, while theExamples are directed to formulations using d-amphetamine base,representative of a low molecular weight drug, and using anacrylic-based adhesive coating, it should be understood that similardrug modulation can be achieved with other active agents, and throughthe use of other polymers and system configurations as discussed.

All studies were conducted relative to a control transdermal deliverysystem, that being a methylphenidate base transdermal delivery system(MethyPatch® produced by the assignee of the instant invention, NovenPharmaceuticals, Inc.), having a known permeation rate, onset andprofile.

All drug-loaded carrier compositions containing d-amphetamine wereprepared using a blend of a non-functional, acrylic-based pressuresensitive adhesive having 75% solids in ethyl acetate and a siliconepressure-sensitive adhesive (BIO-PSA 7-4302). The composition was coatedonto a fluropolymer release liner and dried for in a 76° C. oven toproduce a pressure-sensitive adhesive carrier composition by dry weightof 5% acrylic adhesive, 75% silicone adhesive and 20% drug at a coatweight of about 5 mg/cm².

All non-drug loaded acrylic-based adhesive coatings were prepared usingthe same acrylic adhesive used in preparing the drug-loaded carriercomposition, which was coated onto a polyester backing and dried to acoat weight, for examples 1 and 2, to about 7.5 mg/cm² (example 3 beingdirected to varying coat weights as indicated below) before beingpressure laminated to the drug carrier composition.

Determination of drug flux of the described formulations was conductedon a modified Franz Diffusion cell through a disc of stratum corneumobtained from human cadaver skin. The transdermal system formulationswere die-cut to punched, mounted on the disc, and placed on the cell,which contained an isotonic saline solution. The cells were stored at32° C. for the duration of each flux study while having the solutionstirred at a constant rate of approximately 300 rpm. Samples (n=5) ofthe solution were taken at various time points over the study duration(9 hours), and drug concentrations were determined by high pressureliquid chromatography.

Example 1

In Example 1, two acrylic-based adhesive coatings were prepared thateach contained two different non-functional monomers but in differingratios, 1:1 and 8:2. No effect should have been observed based upon thenon-reactive properties of non-functional acrylic adhesives with drugs.As seen in FIG. 3, the effect of varying the monomeric ratiossignificantly influenced both delivery rate and profile, one being of afirst-order type (fast onset and amount followed by depletion) and theother being near zero-order (“sustained”).

Example 2

In Example 2, three acrylic-based adhesive coatings were prepared thathad differing functionality, one being non-functional and the other twobeing carboxy-functional but with varying concentrations (4% and 8%) ofthe carboxy-functional monomer acrylic acid. As indicated in FIG. 4, thenon-functional acrylic coating imparted the fastest drug onset andhigher drug depletion than either carboxy-functional coating.Furthermore, the use of carboxy-functional monomers decreased drug onsetand provided a near zero-order delivery profile. Accordingly, theaddition of functional moiety to the acrylic coating, in this caseacidic functionality, increasingly diminishes both drug flux and onsetwith increasing carboxy concentrations, but can provide a nearzero-order delivery rate profile.

Example 3

In Example 3, three acrylic-based adhesive coatings were prepared eachusing the acrylic adhesive coating described in Example 2 containing 8%carboxy-functionality but applied to the backing at three differentthickness, about 2.5 mg/cm², about 5 mg/cm² and about 7.5 mg/cm². Asindicated in FIG. 5, the flux rate increases as the acrylic adhesivecoating thickness decreases, while the delivery profile approaches nearzero-order as the acrylic adhesive coating thickness increases.

Other embodiments of the invention will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification beconsidered as exemplary only, with the true scope and spirit of theinvention being indicated by the following claims.

What is claimed is:
 1. A transdermal drug delivery composition,comprising: a backing layer; at least one pressure-sensitive adhesivelayer, having a first surface and a second surface, the first surfacebeing directly affixed to a surface of said backing layer; at least onedrug-containing carrier composition layer comprising a blended mixtureof at least two polymers, each selected from the group consisting ofacrylic-based polymers, silicone-based polymers, rubbers, gums,polyisobutylenes, polyvinylethers, polyurethanes, styrene blockcopolymers, styrenebutadiene polymers, polyether block amide copolymers,ethylene/vinyl acetate copolymers, vinyl acetate based adhesives, andbioadhesives, wherein the drug-containing carrier composition layer hasa first surface and a second surface, the first surface beingco-terminus with and directly affixed to said second surface of one ofsaid at least one pressure-sensitive adhesive layer; and a removablerelease liner directly affixed to said second surface of one of said atleast one drug-containing carrier composition layer, wherein said atleast one drug-containing carrier composition layer includes atherapeutically effective amount of one or more drugs incorporatedtherein.
 2. The transdermal drug delivery composition according to claim1, wherein said pressure-sensitive adhesive layer comprises at least oneacrylic-based polymer.
 3. The transdermal drug delivery compositionaccording to claim 1, wherein said carrier composition layer comprisesat least one acrylic-based adhesive polymer.
 4. The transdermal drugdelivery composition according to claim 3, wherein said carriercomposition layer comprises a blended mixture of at least oneacrylic-based adhesive polymer and at least one second polymer selectedfrom the group consisting of silicone-based polymers, rubbers, gums,polyisobutylenes, polyvinylethers, polyurethanes, styrene blockcopolymers, styrenefbutadiene polymers, polyether block amidecopolymers, ethylene/vinyl acetate copolymers, vinyl acetate basedadhesives, and bioadhesives.
 5. The transdermal drug deliverycomposition according to claim 4, wherein said at least one secondpolymer includes a silicone-based polymer.
 6. The transdermal drugdelivery composition according to claim 4, wherein the acrylic-basedadhesive polymer is present in an amount from about 2% to about 95% ofthe total dry weight of the of the carrier composition layer.
 7. Thetransdermal drug delivery composition according to claim 1, wherein saidcarrier composition layer includes an acrylic-based adhesive polymerwhich is present in an amount from about 2% to about 95% of the totaldry weight of the of the carrier composition layer.
 8. The transdermaldrug delivery composition according to claim 7, wherein saidacrylic-based adhesive polymer is present in an amount from about 2% toabout 85% of the total dry weight of the of the carrier compositionlayer.
 9. The transdermal drug delivery composition according to claim1, wherein said carrier composition layer includes a blended mixturecomprising (i) a first acrylic-based polymer having a firstfunctionality and a first solubility parameter; and (ii) a secondacrylic-based polymer having a second functionality and solubilityparameter, wherein the first and second polymers differ in the amountand type of functional groups, to provide an acrylic-based polymercombination having a net functionality proportional to the ratio of thefirst and second acrylic based polymers used, wherein the polymers arepresent in proportions to provide a net solubility parameter for atleast one of said one or more drugs.
 10. The transdermal drug deliverycomposition according to claim 9, wherein the first acrylic-basedpolymer is present in an amount to provide a flux of at least one of theone or more drugs in the dermal drug delivery composition which isgreater than a composition based solely on the second acrylic-basedpolymer.
 11. The transdermal drug delivery composition according toclaim 10, wherein the amount of the second acrylic-based polymer is inthe range of 5-95 weight % and the amount of the first acrylic-basedpolymer is in the range of 95 to 5% by weight, all based on the totaldry weight of the carrier composition layer.
 12. The transdermal drugdelivery composition according to claim 11, wherein the amount of thesecond acrylic-based polymer is in the range of 20-75 weight % and theamount of the first acrylic-based polymer is in the range of 75 to 20%by weight, all based on the total dry weight of the carrier compositionlayer.
 13. The transdermal drug delivery composition according to claim9, wherein the first acrylic based polymer has substantially nofunctional groups and the second acrylic-based polymer has predeterminedfunctional groups.
 14. The transdermal drug delivery compositionaccording to claim 13, wherein the second acrylic-based polymer hascarboxyl and/or hydroxy functional groups.
 15. The transdermal drugdelivery composition according to claim 13, wherein the secondacrylic-based polymer is present in an amount to provide an increasedsaturation concentration in the dermal drug delivery composition of atleast one of the one or more drugs which is greater than the saturationconcentration of said drug in a composition based solely on the firstacrylic based polymer.
 16. The transdermal drug delivery compositionaccording to claim 9, wherein the functional groups are provided bymonomer units containing functional groups which are incorporated intothe second acrylic-based polymer in an amount of from 0.1 to 20% byweight, based on the dry weight of the second acrylic based polymer. 17.The transdermal drug delivery composition according to claim 16, whereinthe functional monomers are incorporated into the second acrylic-basedpolymer in an amount of from 0.1 to 8% by weight, based on the dryweight of the second acrylic-based polymer.
 18. The transdermal drugdelivery composition according to claim 9, wherein the at least twopolymers contain substantially only the first and second acrylic-basedpolymers.
 19. The transdermal drug delivery composition according toclaim 9, wherein the second acrylic-based polymer includes carboxylfunctional groups.
 20. The transdermal drug delivery compositionaccording to claim 19, wherein the carboxyl functional acrylic-basedpolymer includes 0.1 to 10% by weight of carboxyl functional monomerunits.
 21. The transdermal drug delivery composition according to claim20, wherein the carboxyl functional acrylic-based polymer is acrosslinked vinyl acetate acrylic-based polymer.
 22. The transdermaldrug delivery composition according to claim 1, wherein saidpressure-sensitive adhesive layer includes (i) a first acrylic-basedpolymer having a first functionality; and (ii) a second acrylic-basedpolymer having a second functionality, wherein the first and secondpolymers differ in the amount and type of functional groups, to providean acrylic-based polymer combination having a net functionalityproportional to the ratio of the first and second acrylic based polymersused.
 23. The transdermal drug delivery composition according to claim22, wherein the amount of the second acrylic-based polymer is in therange of 5-95 weight % and the amount of the first acrylic-based polymeris in the range of 95 to 5% by weight, all based on the total dry weightof the carrier composition layer.
 24. The transdermal drug deliverycomposition according to claim 22, wherein the amount of the secondacrylic-based polymer is in the range of 20-75 weight % and the amountof the first acrylic-based polymer is in the range of 75 to 20% byweight, all based on the total dry weight of the carrier compositionlayer.
 25. The transdermal drug delivery composition according to claim22, wherein the first acrylic based polymer has substantially nofunctional groups and the second acrylic-based polymer has predeterminedfunctional groups.
 26. The transdermal drug delivery compositionaccording to claim 25, wherein the second acrylic-based polymer hascarboxyl and/or hydroxy functional groups.
 27. The transdermal drugdelivery composition according to claim 22, wherein the functionalgroups are provided by monomer units containing functional groups whichare incorporated into the second acrylic-based polymer in an amount offrom 0.1 to 20% by weight, based on the dry weight of the second acrylicbased polymer.
 28. The transdermal drug delivery composition accordingto claim 27, wherein the functional monomers are incorporated into thesecond acrylic-based polymer in an amount of from 0.1 to 8% by weight,based on the dry weight of the second acrylic-based polymer.
 29. Thetransdermal drug delivery composition according to claim 22, wherein theat least two polymers contain substantially only the first and secondacrylic-based polymers.
 30. The transdermal drug delivery compositionaccording to claim 22, wherein the second acrylic-based polymer includescarboxyl functional groups.
 31. The transdermal drug deliverycomposition according to claim 30, wherein the carboxyl functionalacrylic-based polymer includes 0.1 to 10% by weight of carboxylfunctional monomer units.
 32. The transdermal drug delivery compositionaccording to claim 31, wherein the carboxyl functional acrylic-basedpolymer is a crosslinked vinyl acetate acrylic-based polymer.
 33. Thetransdermal drug delivery composition according to claim 1, wherein saidpressure-sensitive adhesive layer includes a blend of (i) anacrylic-based polymer; and (ii) at least one second polymer selectedfrom the group consisting of silicone-based polymers, rubbers, gums,polyisobutylenes, polyvinylethers, polyurethanes, styrene blockcopolymers, styrenelbutadiene polymers, polyether block amidecopolymers, ethylene/vinyl acetate copolymers, vinyl acetate basedadhesives, and bioadhesives.
 34. The transdermal drug deliverycomposition according to claim 33, wherein said second polymer includesa silicone-based polymer.
 35. The transdermal drug delivery compositionaccording to claim 1, wherein said pressure-sensitive adhesive layer hasa coat weight of from about 2.5 to about 15 mg/cm².
 36. The transdermaldrug delivery composition according to claim 35, wherein saidpressure-sensitive adhesive coating layer has a coat weight of fromabout 2.5 to about 7.5 mg/cm².
 37. The transdermal drug deliverycomposition according to claim 1, wherein said pressure-sensitiveadhesive layer includes at least one acrylic-based polymer and whereinsaid acrylic based polymer is composed of at least 50% by weight of anacrylate or alkyl acrylate monomer, from 0 to 20% of a functionalmonomer copolymerizable with the acrylate, and from 0 to 40% of othermonomers.
 38. The transdermal drug delivery composition according toclaim 37, wherein said acrylate or alkyl acrylate-monomer includesacrylic acid, methacrylic acid, butyl acrylate, butyl methacrylate,hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate, 2-ethylbutylmethacrylate, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexylacrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate,dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, and tridecylmethacrylate.
 39. The transdermal drug delivery composition according toclaim 38, wherein said functional monomer is a monomer selected from thegroup consisting of methacrylic acid, maleic acid, maleic anhydride,hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide,dimethylacrylamide, acrylonitrile, dimethylaminoethyl acrylate,dimethylaminoethyl methacrylate, tertbutylaminoethyl acrylate,tert-butylaminoethyl methacrylate, methoxyethyl acrylate andmethoxyethyl methacrylate.
 40. A transdermal drug delivery composition,comprising: a backing layer; at least one pressure-sensitive adhesivelayer, having a first surface and a second surface, the first surfacebeing directly affixed to a surface of said backing layer; at least onedrug-containing carrier composition layer comprising a blended mixtureof at least two polymers, each selected from the group consisting ofacrylic-based adhesive polymers, silicone-based polymers, rubbers, gums,polyisobutylenes, polyvinylethers, polyurethanes, styrene blockcopolymers, styrenebutadiene polymers, polyether block amide copolymers,ethylene/vinyl acetate copolymers, vinyl acetate based adhesives, andbioadhesives, said drug-containing carrier composition layer having afirst surface and a second surface, the first surface being co-terminuswith and directly affixed to a said second surface of one of said atleast one pressure-sensitive adhesive layer; and a removable releaseliner directly affixed to said second surface of one of said at leastone drug-containing carrier composition layer, wherein said at least onedrug-containing carrier composition layer includes a therapeuticallyeffective amount of one or more drugs incorporated therein; made by aprocess comprising: (a) forming said at least one pressure-sensitiveadhesive layer affixed to said backing layer, wherein saidpressure-sensitive adhesive layer is formed without any drug; (b)forming said at least one drug-containing carrier layer affixed to saidrelease liner; (c) affixing said second surface of one of said at leastone pressure-sensitive adhesive layer as formed without any drug to saidfirst surface of one of said at least one drug-containing carrier layer;(d) optionally, if necessary, cutting said at least onepressure-sensitive adhesive layer and said at least one drug-containingcarrier layer such that said layers are co-terminus.
 41. The transdermaldrug delivery composition according to claim 1, wherein said carriercomposition layer comprises a pressure-sensitive adhesive.